Palbociclib regimen extends PFS in double-positive metastatic breast cancer
Click Here to Manage Email Alerts
Key takeaways:
- The addition of palbociclib to anti-HER2 and endocrine therapy extended PFS by more than a year.
- The regimen appeared well tolerated, according to investigators.
SAN ANTONIO — The addition of palbociclib to standard care extended median PFS for patients with hormone receptor-positive, HER2-positive metastatic breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
The randomized phase 3 PATINA trial is the first phase 3 study to show the benefit of cyclin-dependent kinase (CDK) 4/6 inhibition in this setting, according to principal investigator Otto Metzger, MD, medical oncologist at Dana-Farber Cancer Institute.
The combination “may represent a new standard of care” for this population, Metzger added.
An estimated 10% of breast cancer cases are hormone receptor positive and HER2 positive. Anti-HER2 therapies have improved outcomes considerably. However, resistance remains inevitable for most patients with HER2-positive disease, Metzger said.
There is a need for new treatment strategies for what is often called double-positive breast cancer, and there is “a very strong rationale” for blocking CDK 4/6 in HER2-positive disease, Metzger said.
Palbociclib (Ibrance, Pfizer), a CDK 4/6 inhibitor, is approved in the United States for use with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women or men with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. The agent also is approved for use with fulvestrant for patients whose disease progresses after endocrine therapy.
The PATINA study included 518 patients (median age, 53.4 years; range, 44.2-61.4; 91.7% white; 99.4% women) with hormone receptor-positive, HER2-positive metastatic breast cancer.
Trial participants had received six to eight cycles of induction chemotherapy plus trastuzumab (Herceptin, Genentech), with or without pertuzumab (Perjeta, Genentech), and they had no evidence of disease progression after induction chemotherapy. The majority (97.3%) of study participants had received prior pertuzumab.
Researchers assigned 261 patients to first-line maintenance with palbociclib plus anti-HER2 therapy — trastuzumab with or without pertuzumab — and endocrine therapy. The other 257 patients received anti-HER2 and endocrine therapy alone.
Treatment continued until disease progression or unacceptable toxicity.
PFS per investigator assessment served as the primary endpoint. OS served as a secondary endpoint.
Results showed improved investigator-assessed PFS in the palbociclib group (median, 44.3 months vs. 29.1 months; HR = 0.74; 95% CI, 0.58-0.94).
“We see the curves stay separated and remain this way over many years of follow-up, with almost a 10% benefit in absolute terms at 60 months,” Metzger said.
The PFS benefit appeared consistent among subgroups based on receipt of prior anti-HER2 therapy (yes, HR = 0.76; 95% CI, 0.57-1.01; no, HR = 0.68; 95% CI, 0.54-1.07), as well as best response to induction (complete/partial response, HR = 0.76; 95% CI, 0.57-1.02; stable disease, HR = 0.72; 95% CI, 0.47-1.12).
Analyses of investigator-assessed confirmed overall response rate (29.9% vs. 22.2%; P = .046) and clinical benefit rate (89.3% vs. 81.3%; P = .01) also favored the palbociclib regimen.
OS data remained immature, as only 119 of the planned 247 events needed for analysis had occurred. However, an interim analysis showed a higher percentage of patients in the palbociclib group survived 3 years (87% vs. 84.7%) and 5 years (74.3% vs. 68.8%; HR = 0.86; 95% CI, 0.6-1.24).
Researchers reported no statistically significant difference in incidence of grade 4 or higher adverse events between the palbociclib and control groups (12.3% vs. 8.9%).
Adverse events that occurred more frequently in the palbociclib group included neutropenia (grade 3/grade 4, 67.8% vs. 4.4%), decreased white blood cell count (grade 3/grade 4, 11.9% vs. 0%), fatigue (grade 3, 5.4% vs. 0%) and diarrhea (grade 3, 11.1% vs. 1.6%).
Fourteen patients (7.5%) in the palbociclib group discontinued treatment due to adverse events.
No treatment-related deaths occurred in either study arm.
“Our results reinforce the strong scientific rationale for overcoming resistance to anti-HER2 therapy and endocrine therapy by adding CDK 4/6 inhibition,” Metzger said. “[This trial] demonstrates a clinically meaningful improvement in PFS among patients diagnosed with hormone receptor-positive, HER2-positive breast cancer. The median PFS in the control room being 29.1 months far exceeded our expectations, and despite that, we see an improvement of greater than a year once we add palbociclib to this regimen.”
The results will be shared with the FDA and other regulatory agencies, Metzger said.
“We feel these data are compelling and that this regimen should be widely available [for these patients],” he said.
Perspective
Back to Top
Antoinette R. Tan, MD, MHSc
CDK 4/6 inhibitors have significantly transformed the first-line treatment of metastatic hormone receptor-positive, HER2-negative breast cancer since 2015. Several phase 3 studies have demonstrated that treatment with the combination of a CDK4/6 inhibitor and endocrine therapy, as opposed to endocrine therapy alone, is associated with longer OS, longer PFS and better objective response rates. This firmly established CDK4/6 inhibitors in the treatment of hormone receptor-positive, HER2-negative advanced breast cancer.The results of the phase 3 PATINA trial now indicate a potential role for a CDK4/6 inhibitor in combination with endocrine therapy and anti-HER2 drugs in the first-line treatment of hormone receptor-positive, HER2-positive metastatic breast cancer without disease progression after the completion of chemotherapy induction.
Patients treated with palbociclib, HER2 blockade and endocrine therapy achieved a slightly higher 5-year PFS rate than the control group (43.2% vs. 33.4%). Of importance is the manageable toxicity profile of the CDK4/6 inhibitor-based triplet combination therapy. The low discontinuation rate (7.5%) is reassuring. We await the maturation of OS data.
Right-sizing systemic therapy for hormone receptor-positive, HER2-positive metastatic breast cancer is a welcomed approach. In the PATINA trial, the strategy of targeting multiple pathways (eg, ER, HER2 and CDK4/6) during the maintenance phase is biologically sound, and other clinical trials are adopting a similar approach. One example is the phase 3 INAVO122 trial, which is evaluating a combined regimen of dual HER2-targeted agent with a phosphatidylinositol 3-kinase (PI3K) inhibitor. In this study, the addition of the PI3 kinase inhibitor inavolisib (Itovebi, Genentech) to a standard anti-HER2 therapeutic regimen during the maintenance phase after first-line induction chemotherapy is being assessed for patients with HER2-positive metastatic breast cancer who harbor a PIK3CA mutation.
Another merit of the PATINA trial is its elucidation of how maintenance therapy for patients with HER2-positive advanced disease can be modified to improve clinical outcomes while maintaining quality of life, especially when first-line treatment may be shifting toward the use of antibody-drug conjugates for induction therapy. Overall, it is encouraging news for our patients with triple-positive metastatic breast cancer that the combination regimen of palbociclib, anti-HER2 agents, and endocrine therapy offers PFS benefit, with a favorable toxicity profile, and could be a viable maintenance treatment strategy.
Collapse
Metzger O, et al. GS2-12. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio.
Click Here to Manage Email Alerts